Principal Signal Research Articles

22. Comparison of the methods for brain parcellation

In recent studies many scientists tend to examine functional connectivity with the help of graph theory algorithms, especially when studying resting-state fMRI data. The graph theory approach is based on the cortex parcellation – dividing it to disjoint areas and analyzing the relations between these areas. This work tries to compare results of parcellation by three types of anatomical atlases – AAL atlas, atlas of Brodmann areas and parcellation to gyri and sulci. We also use different approaches to compute representative signal for each area and compare how the representative explains data. We used mean signal, first, second and third principal component as the typical signal and we computed significances of each representative type by percentage of area variability explained by this signal. We found that the representative explains less than 50% of the variability in the area no matter which type of representative we chose. This could have been caused by present noise or the area size. The representative created from mean signal is almost the same as the first principal component signal regarding the percentage of explained variability. However, 1st PCA component can capture the inhomogeneity of the area and therefore can suggest possible dividing of the area which would result in smaller areas better explained by their separate representatives. Our comparison of anatomical atlases brought one compex conclusion – areas created according to Brodmann and AAL atlases have lower mean variance and higher mean explained variabillity than areas specified by atlas of gyri and sulci. To conclude we propose to use the AAL atlas above the other two types of atlases. In future the comparison of parcellation by anatomical atlases and data driven analysis would be interesting.

Multivariate Control Charts for Simultaneous Quality Monitoring of Isoniazid and Rifampicin in a Pharmaceutical Formulation Using a Portable Near Infrared Spectrometer

One of the keys to maintain high manufacturing quality improvement is the use of control charts. In this work, multivariate control charts based on significant principal component (PC) scores and net analytical signal (NAS) were developed to simultaneously monitor the quality of two active pharmaceutical ingredients (API) (isoniazid and rifampicin) in pharmaceutical formulation (laboratory samples and production samples) using a portable near infrared spectrometer. The limits for both multivariate charts were estimated using the quality specifications from the pharmaceutical formulation (± 5% of the nominal content of each API). The use of these multivariate control charts has provided a simple and powerful tool to evaluate the content of pharmaceutical formulations based on isoniazid and rifampicin capsules combined with near infrared spectroscopy. The procedure is rapid and adjustable for monitoring the production of the pharmaceutical preparations produced at UFRN/Brazil toward the process analytical technology (PAT) for the treatment of pulmonary tuberculosis.

Continuous Gravity Monitoring for CO2 Geo-sequestration (2) a Case Study at the Farnsworth CO2-EOR Field

We started continuous gravity monitoring using superconducting gravimeter at the Farnsworth CO2-EOR field. During the baseline measurements we detected the obvious decreasing trend, which is attributed to changes in the local water table. The CO2-EOR process will result in the redistribution of mass which may result in gravity signals, which is the principal signal of interest for this study. We must revise the observation plan to detect the subtle signals as precious as possible. With two SGs located in near sites making parallel SG and SG measurements can provide improved accuracy and sensitivity.

Genetic Advances in Ophthalmology: The Role of Melanopsin-Expressing, Intrinsically Photosensitive Retinal Ganglion Cells in the Circadian Organization of the Visual System

Daily changes in the light-dark cycle are the principal environmental signal that enables organisms to synchronize their internal biology with the 24-hour day–night cycle. In humans, the visual system is integral to photoentrainment and is primarily driven by a specialized class of intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the photopigment melanopsin (OPN4) in the inner retina. These cells project through the retinohypothalamic tract (RHT) to the suprachiasmatic nuclei (SCN) of the hypothalamus, which serves as the body’s master biological clock. At the same time, the retina itself possesses intrinsic circadian oscillations, exemplified by diurnal fluctuations in visual sensitivity, neurotransmitter levels, and outer segment turnover rates. Recently, it has been noted that both central and peripheral oscillators share a molecular clock consisting of an endogenous, circadian-driven, transcription–translation feedback loop that cycles with a periodicity of approximately 24 hours. This review will cover the role that melanopsin and ipRGCs play in the circadian organization of the visual system.

Mutations in DSTYK and Dominant Urinary Tract Malformations

BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine–threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.)

Emerging non-canonical functions for heterotrimeric G proteins in cellular signaling

Classically heterotrimeric G proteins have been described as the principal signal transducing machinery for G-protein-coupled receptors. Receptor activation catalyzes nucleotide exchange on the Gα protein, enabling Gα-GTP and Gβγ-subunits to engage intracellular effectors to generate various cellular effects such as second messenger production or regulation of ion channel conductivity. Recent genetic and proteomic screens have identified novel heterotrimeric G-protein-interacting proteins and expanded their functional roles. This review highlights some examples of recently identified interacting proteins and summarizes how they functionally connect heterotrimeric G proteins to previously underappreciated cellular roles.

Hypoxia Immunity, Metabolism, and Hyperthermia

Hypoxia is common in solid tumors and in many other disease states such as myocardial infarction, stroke, bone fracture, and pneumonitis. Once hypoxia has developed, the undernourished and hypoxic cells trigger signals in order to obtain new blood vessels to satisfy their increasing demands and to resolve hypoxia. The principal signal activated is an ancestral oxygen sensor, the hypoxia inducible factor (HIF). After its nuclear translocation, HIF triggers a series of mediators that recruit, into the hypoxic milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells. Resident and recruited cells participate in the processes of neoangiogenesis, for resolving the hypoxia, while at the same time trigger an inflammatory reaction. The inflammatory reaction has as primary end point, the repair of the damaged area, but if an insufficient production of resolvins is produced, the inflammatory reaction becomes chronic and is unable to repair the damaged tissue. In this brief overview, we will show the differences and the similar events present in cancer, myocardial infarction, and stroke. Furthermore, the metabolic alterations produced in the tumor by hypoxia/HIF axis and the consequences on hyperthermic treatment are also discussed.

Cognitive Performance as a Zeitgeber: Cognitive Oscillators and Cholinergic Modulation of the SCN Entrain Circadian Rhythms

The suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals that can synchronize or entrain to environmental cues. Although light exerts powerful influences on SCN output, other non-photic stimuli can modulate the SCN as well. We recently demonstrated that daily performance of a cognitive task requiring sustained periods of attentional effort that relies upon basal forebrain (BF) cholinergic activity dramatically alters circadian rhythms in rats. In particular, normally nocturnal rats adopt a robust diurnal activity pattern that persists for several days in the absence of cognitive training. Although anatomical and pharmacological data from non-performing animals support a relationship between cholinergic signaling and circadian rhythms, little is known about how endogenous cholinergic signaling influences SCN function in behaving animals. Here we report that BF cholinergic projections to the SCN provide the principal signal allowing for the expression of cognitive entrainment in light-phase trained animals. We also reveal that oscillator(s) outside of the SCN drive cognitive entrainment as daily timed cognitive training robustly entrains SCN-lesioned arrhythmic animals. Ablation of the SCN, however, resulted in significant impairments in task acquisition, indicating that SCN-mediated timekeeping benefits new learning and cognitive performance. Taken together, we conclude that cognition entrains non-photic oscillators, and cholinergic signaling to the SCN serves as a temporal timestamp attenuating SCN photic-driven rhythms, thereby permitting cognitive demands to modulate behavior.

Abstract TP267: Metabolomics Identifies a Branched Chain Amino Acid Profile in Acute Ischemic Stroke

Background: There is limited information about changes in metabolism during acute ischemic stroke. The identification of circulating plasma metabolites modulated during cerebral infarction may provide insight into pathogenesis and identify novel biomarkers. Methods: We performed filament occlusion of the middle cerebral artery of Wistar rats compared to sham controls, collecting plasma and CSF two hours after onset of ischemia. Plasma samples from human acute stroke and TIA control subjects were also collected an average of 6 hours after stroke onset. All samples were analyzed using liquid chromatography followed by tandem mass spectrometry. Positively charged metabolites including amino acids, nucleotides and neurotransmitters were quantified using electrospray ionization followed by scheduled multiple reaction monitoring. Results: Several metabolites were altered in the setting of cerebral ischemia. We detected a 42% rise in glucose (P=0.006) in stroke subjects compared to TIA controls, consistent with prior observations. We confirmed the validity of the method by comparing glucose measured in our metabolomics platform to bedside glucometer measurements, and we found a correlation coefficient of 0.72 (P<0.0001). We also detected a consistent reduction in branched chain amino acids (BCAAs; valine, leucine, isoleucine) in rat plasma, rat CSF and human plasma compared to the respective controls. We detected a 17% decrease in the level of the branched chain amino acids (P<0.00005). In the human stroke cohort, lower BCAA level correlated with poor neurological outcome (mRS 3-6; Spearman correlation = -0.39, P=0.001). Conclusions: Our data support a role for BCAAs in ischemic stroke, which correlates with worse neurological outcome. Intriguingly, BCAAs serve an integral role in the glutamate/glutamine cycle between astrocytes and neurons, and are also a principal signal for energy homeostasis. The extent to which BCAAs are in a causal pathway or are an epi-phenomenon of ischemic stroke remains to be determined.

Building the gateway to consciousness—about the development of the thalamus

The thalamus is a twinned bulb-shaped structures that form at the top of the brainstem on either side of the third ventricle. The thalamic complex is located in the posterior forebrain and includes the prethalamus and thalamus (formerly known as ventral thalamus and dorsal thalamus, respectively). This complex is the major sensory relay station of the brain, receiving all inputs (except olfaction) and connecting reciprocally with the overlying cortex therefore, Crick and Koch (2003) has described the thalamus as “the gateway to consciousness.” Although, the thalamus has been anatomically characterized in vertebrates the underlying genetic mechanism leading to the formation of this complex brain area is largely unknown. In this special issue we tried to cover many aspects describing the development of the posterior forebrain i.e., the thalamus. The posterior forebrain can be subdivided in the epithalamus, the prethalamus (Figure ​(Figure1,1, indicated in yellow), the thalamus (Figure ​(Figure1,1, indicated in green), and the pretectum. Mechanisms regulating the formation and setting the boundaries between them are described in the article of Chatterjee and Li (2012). The crucial structure for the development of the thalamus is a small group of cells secreting different signaling molecules and is localized at the intrathalamic boundary, the zona limitans intrathalamica (ZLI). This cell population has been termed the mid-diencephalic organizer (MDO) or alternatively as ZLI organizer. The MDO releases three different families of signaling factors, Shh, Wnt, and Fgf. This network has been described in the articles of Hagemann and Scholpp (2012) focusing mainly on events in zebrafish and in Martinez-Ferre and Martinez (2012), who describe the situation in chick. Both group described that the principal signal of the MDO is Shh, which is conserved in different animals (Figure ​(Figure1,1, expression domain of Shh indicated in red). Therefore, we elucidate the function of Shh in mice more in detail in two articles. Epstein (2012) focuses in his article on the description of the function of this signaling factor, whereas Haddad-Tovolli et al. (2012) focuses on the regulators downstream of Shh signaling, the GLI transcription factors. Pre-patterning of the thalamic tissue is essential for the axonal projections of the thalamus and the most important axonal output of this structure is the thalamo-cortical projection. Price et al. (2012) and Grant et al. (2012) review recent progress of the development of these projections and axonal guidance. The zebrafish serves as a novel vertebrate model organism in thalamic development, however, the comparability to the mammalian systems is difficult. In a comparative review (Mueller, 2012) summarizes anatomical similarities and differences of the thalamus in different model organisms. Dorsally adjacent to the thalamus is the location of the habenula. The development of the connection to the thalamic tissue has been elucidated by two articles from Beretta et al. (2012) and Aizawa et al. (2011). Figure 1 Development of the thalamus in vertebrates. After our opinion, the special issue “Building the gateway to consciousness—about the development of the thalamus” summarizes recent efforts in understanding the formation of thalamus in vertebrates and we carefully selected carefully articles covering the entire field. However, it is impossible to elucidate any aspect in sufficient detail and we would like to apologize to our colleagues for potential gaps. We wish all scientist as much as fun in reading the articles as we had in assembling it and sincerely hope that this special issue helps the field of thalamus development to find the scientific recognition it deserves.

G-CSF-activated STAT3 enhances production of the chemokine MIP-2 in bone marrow neutrophils

Neutrophil mobilization from the bone marrow is a critical aspect of the innate immune response, enabling a rapid deployment of phagocytes to infected or inflamed tissue. The cytokine G-CSF, which is induced rapidly during infection, elicits a swift and potent mobilizing response, yet its mechanisms of action remain poorly understood. Here, we studied the role of G-CSF and its principal signal transducer STAT3 in regulating expression of the neutrophil chemoattractant MIP-2. Our studies revealed Gr-1(hi) mature neutrophils as major sources of Cxcl2 (MIP-2) mRNA in bone marrow and G-CSF-responsive MIP-2 protein production. Induction of Cxcl2 was regulated directly by G-CSF-activated STAT3 via interaction at a STAT consensus element in the Cxcl2 promoter. G-CSF coordinately stimulated the association of STAT3, induction of the transcriptionally active H3K4me3 modification, and recruitment of RNA Pol II at the Cxcl2 proximal promoter, as well as the promoter region of Il8rb, encoding the MIP-2 receptor. These results suggest that the G-CSF-STAT3 pathway directly regulates transcriptional events that induce neutrophil mobilization.

Calcium Feedback to cGMP Synthesis Strongly Attenuates Single-Photon Responses Driven by Long Rhodopsin Lifetimes

Rod photoreceptors generate amplified, reproducible responses to single photons via a G protein signaling cascade. Surprisingly, genetic perturbations that dramatically alter the deactivation of the principal signal amplifier, the GPCR rhodopsin (R∗), do not much alter the amplitude of single-photon responses (SPRs). These same perturbations, when crossed into a line lacking calcium feedback regulation of cGMP synthesis, produced much larger alterations in SPR amplitudes. Analysis of SPRs from rods with and without feedback reveal that the consequences of trial-to-trial fluctuations in R∗ lifetime in normal rods are also dampened by feedback regulation of cGMP synthesis. Thus, calcium feedback trumps the mechanisms of R∗ deactivation in determining the SPR amplitude, attenuating responses arising from longer R∗ lifetimes to a greater extent than those arising from shorter ones. As a result, rod SPRs achieve a more stereotyped amplitude, a characteristic considered important for reliable transmission through the visual system.

A Novel Nuclear Trafficking Module Regulates the Nucleocytoplasmic Localization of the Rabies Virus Interferon Antagonist, P Protein

Regulated nucleocytoplasmic transport of proteins is central to cellular function and dysfunction during processes such as viral infection. Active protein trafficking into and out of the nucleus is dependent on the presence within cargo proteins of intrinsic specific modular signals for nuclear import (nuclear localization signals, NLSs) and export (nuclear export signals, NESs). Rabies virus (RabV) phospho (P) protein, which is largely responsible for antagonising the host anti-viral response, is expressed as five isoforms (P1-P5). The subcellular trafficking of these isoforms is thought to depend on a balance between the activities of a dominant N-terminal NES (N-NES) and a distinct C-terminal NLS (C-NLS). Specifically, the N-NES-containing isoforms P1 and P2 are cytoplasmic, whereas the shorter P3-P5 isoforms, which lack the N-NES, are believed to be nuclear through the activity of the C-NLS. Here, we show for the first time that RabV P contains an additional strong NLS in the N-terminal region (N-NLS), which, intriguingly, overlaps with the N-NES. This arrangement represents a novel nuclear trafficking module where the N-NLS is inactive in P1 but becomes activated in P3, concomitant with truncation of the N-NES, to become the principal targeting signal conferring nuclear accumulation. Understanding this unique switch arrangement of overlapping, co-regulated NES/NLS sequences is vital to delineating the critical role of RabV P protein in viral infection.

Myosin Regulatory Light Chain Diphosphorylation Slows Relaxation of Arterial Smooth Muscle

The principal signal to activate smooth muscle contraction is phosphorylation of the regulatory light chains of myosin (LC(20)) at Ser(19) by Ca(2+)/calmodulin-dependent myosin light chain kinase. Inhibition of myosin light chain phosphatase leads to Ca(2+)-independent phosphorylation at both Ser(19) and Thr(18) by integrin-linked kinase and/or zipper-interacting protein kinase. The functional effects of phosphorylation at Thr(18) on steady-state isometric force and relaxation rate were investigated in Triton-skinned rat caudal arterial smooth muscle strips. Sequential phosphorylation at Ser(19) and Thr(18) was achieved by treatment with adenosine 5'-O-(3-thiotriphosphate) in the presence of Ca(2+), which induced stoichiometric thiophosphorylation at Ser(19), followed by microcystin (phosphatase inhibitor) in the absence of Ca(2+), which induced phosphorylation at Thr(18). Phosphorylation at Thr(18) had no effect on steady-state force induced by Ser(19) thiophosphorylation. However, phosphorylation of Ser(19) or both Ser(19) and Thr(18) to comparable stoichiometries (0.5 mol of P(i)/mol of LC(20)) and similar levels of isometric force revealed differences in the rates of dephosphorylation and relaxation following removal of the stimulus: t(½) values for dephosphorylation were 83.3 and 560 s, and for relaxation were 560 and 1293 s, for monophosphorylated (Ser(19)) and diphosphorylated LC(20), respectively. We conclude that phosphorylation at Thr(18) decreases the rates of LC(20) dephosphorylation and smooth muscle relaxation compared with LC(20) phosphorylated exclusively at Ser(19). These effects of LC(20) diphosphorylation, combined with increased Ser(19) phosphorylation (Ca(2+)-independent), may underlie the hypercontractility that is observed in response to certain physiological contractile stimuli, and under pathological conditions such as cerebral and coronary arterial vasospasm, intimal hyperplasia, and hypertension.

Lysine 63 -linked ubiquitylation of PIN2 auxin carrier protein governs hormonally controlled adaptation of Arabidopsis root growth

Cross-talk between plant cells and their surroundings requires tight regulation of information exchange at the plasma membrane (PM), which involves dynamic adjustments of PM protein localization and turnover to modulate signal perception and solute transport at the interface between cells and their surroundings. In animals and fungi, turnover of PM proteins is controlled by reversible ubiquitylation, which signals endocytosis and delivery to the cell's lytic compartment, and there is emerging evidence for related mechanisms in plants. Here, we describe the fate of Arabidopsis PIN2 protein, required for directional cellular efflux of the phytohormone auxin, and identify cis- and trans-acting mediators of PIN2 ubiquitylation. We demonstrate that ubiquitin acts as a principal signal for PM protein endocytosis in plants and reveal dynamic adjustments in PIN2 ubiquitylation coinciding with variations in vacuolar targeting and proteolytic turnover. We show that control of PIN2 proteolytic turnover via its ubiquitylation status is of significant importance for auxin distribution in root meristems and for environmentally controlled adaptations of root growth. Moreover, we provide experimental evidence indicating that PIN2 vacuolar sorting depends on modification specifically by lysine(63)-linked ubiquitin chains. Collectively, our results establish lysine(63)-linked PM cargo ubiquitylation as a regulator of polar auxin transport and adaptive growth responses in higher plants.

Sensitivity to temporal modulation rate and spectral bandwidth in the human auditory system: fMRI evidence

Hierarchical models of auditory processing often posit that optimal stimuli, i.e., those eliciting a maximal neural response, will increase in bandwidth and decrease in modulation rate as one ascends the auditory neuraxis. Here, we tested how bandwidth and modulation rate interact at several loci along the human central auditory pathway using functional MRI in a cardiac-gated, sparse acquisition design. Participants listened passively to both narrowband (NB) and broadband (BB) carriers (1/4- or 4-octave pink noise), which were jittered about a mean sinusoidal amplitude modulation rate of 0, 3, 29, or 57 Hz. The jittering was introduced to minimize stimulus-specific adaptation. The results revealed a clear difference between spectral bandwidth and temporal modulation rate: sensitivity to bandwidth (BB > NB) decreased from subcortical structures to nonprimary auditory cortex, whereas sensitivity to slow modulation rates was largest in nonprimary auditory cortex and largely absent in subcortical structures. Furthermore, there was no parametric interaction between bandwidth and modulation rate. These results challenge simple hierarchical models, in that BB stimuli evoked stronger responses in primary auditory cortex (and subcortical structures) rather than nonprimary cortex. Furthermore, the strong preference for slow modulation rates in nonprimary cortex demonstrates the compelling global sensitivity of auditory cortex to modulation rates that are dominant in the principal signals that we process, e.g., speech.

Mapping Structural Determinants within Third Intracellular Loop That Direct Signaling Specificity of Type 1 Corticotropin-releasing Hormone Receptor

The type 1 corticotropin-releasing hormone receptor (CRH-R1) influences biological responses important for adaptation to stressful stimuli, through activation of multiple downstream effectors. The structural motifs within CRH-R1 that mediate G protein activation and signaling selectivity are unknown. The aim of this study was to gain insights about important structural determinants within the third intracellular loop (IC3) of the human CRH-R1α important for cAMP and ERK1/2 pathways activation and selectivity. We investigated the role of the juxtamembrane regions of IC3 by mutating amino acid cassettes or specific residues to alanine. Although simultaneous tandem alanine mutations of both juxtamembrane regions Arg(292)-Met(295) and Lys(311)-Lys(314) reduced ligand binding and impaired signaling, all other mutant receptors retained high affinity binding, indistinguishable from wild-type receptor. Agonist-activated receptors with tandem mutations at the proximal or distal terminal segments enhanced activation of adenylyl cyclase by 50-75% and diminished activation of inositol trisphosphate and ERK1/2 by 60-80%. Single Ala mutations identified Arg(292), Lys(297), Arg(310), Lys(311), and Lys(314) as important residues for the enhanced activation of adenylyl cyclase, partly due to reduced inhibition of adenylyl cyclase activity by pertussis toxin-sensitive G proteins. In contrast, mutation of Arg(299) reduced receptor signaling activity and cAMP response. Basic as well as aliphatic amino acids within both juxtamembrane regions were identified as important for ERK1/2 phosphorylation through activation of pertussis toxin-sensitive G proteins as well as G(q) proteins. These data uncovered unexpected roles for key amino acids within the highly conserved hydrophobic N- and C-terminal microdomains of IC3 in the coordination of CRH-R1 signaling activity.

Near infrared spectroscopy combined with least squares support vector machines and fuzzy rule-building expert system applied to diagnosis of endometrial carcinoma

Objective: The feasibility of early diagnosis of endometrial carcinoma was studied by least squares support vector machines (LS-SVM) and fuzzy rule-building expert system (FuRES) that classified near infrared (NIR) spectra of tissues. Methods: NIR spectra of 77 specimens of endometrium were collected. The spectra were pretreated by principal component orthogonal signal correction (PC-OSC) and direct orthogonal signal correction (DOSC) methods to improve the signal-to-noise ratio (SNR) and remove the influences of background and baseline. The effects of modeling parameters were investigated using bootstrapped Latin-partition methods. Results: The optimal LS-SVM model of the PC-OSC pretreatment method successfully classified the samples with prediction accuracies of 96.8±1.4%. Conclusions: The proposed procedure proved to be rapid and convenient, which is suitable to be developed as a non-invasive diagnosis method for cancer tissue.

Gift-exchange, incentives, and heterogeneous workers

By incorporating reciprocity in an otherwise standard principal–agent model, I investigate the relation between monetary gift-exchange and incentive pay, while allowing for worker heterogeneity. I assume that some, but not all, workers care more for their principal when they are convinced that the principal cares for them. The principal can be egoistic or altruistic. Absent worker heterogeneity, an altruistic principal signals his altruism by offering relatively weak incentives and a relatively high expected total compensation. However, the latter is not always required to credibly signal altruism. Furthermore, since some workers do not reciprocate the principalʼs altruism, the principal may find it optimal to write a contract that simultaneously signals his altruism and screens reciprocal worker types. Such a contract is characterised by excessively strong incentives and a relatively high expected total compensation.

Cytokinin Modulates Endocytic Trafficking of PIN1 Auxin Efflux Carrier to Control Plant Organogenesis

Cytokinin is an important regulator of plant growth and development. In Arabidopsis thaliana, the two-component phosphorelay mediated through a family of histidine kinases and response regulators is recognized as the principal cytokinin signal transduction mechanism activating the complex transcriptional response to control various developmental processes. Here, we identified an alternative mode of cytokinin action that uses endocytic trafficking as a means to direct plant organogenesis. This activity occurs downstream of known cytokinin receptors but through a branch of the cytokinin signaling pathway that does not involve transcriptional regulation. We show that cytokinin regulates endocytic recycling of the auxin efflux carrier PINFORMED1 (PIN1) by redirecting it for lytic degradation in vacuoles. Stimulation of the lytic PIN1 degradation is not a default effect for general downregulation of proteins from plasma membranes, but a specific mechanism to rapidly modulate the auxin distribution in cytokinin-mediated developmental processes.